The overarching goal of this proposal is to better understand how pre-existing cardiovascular risk factors interact with cardiotoxic therapies to heighten the risk of developing major cardiac events among lymphoma survivors. Cardiovascular disease is a leading cause of premature mortality among cancer survivors. Cardiovascular risk arises predominantly from cancer treatments, and hypertension, dyslipidemia, and diabetes contribute to this risk. The current proposal focuses on the development of major cardiovascular events among survivors of aggressive lymphoma. We aim to investigate the interaction of pre-existing cardiovascular risk factors and cardiotoxic therapie on major cardiovascular events. There is preliminary evidence for these interactions among survivors of childhood cancer, but they have never been systematically investigated in adult cancers. Aim 1 focuses on how cardiovascular risk factors interact with anthracyclines, which can damage the heart and its cardiovascular system to increase risk for heart failure, myocardial infarction, and stroke. Aim 2 focuses on how cardiovascular risk factors interact with radiation to the neck, which can contribute to the risk of stroke, and with radiation to the chest, which can contribute to heart failure and myocardial infarction. Aggressive lymphoma is an ideal paradigm for investigating these interactions, because there is a large population of survivors who were treated with key cardiotoxic therapies and who later experience significant cardiovascular morbidity and mortality. Further, many are diagnosed late enough that cardiovascular risk factors are common. To investigate whether cardiovascular risk factors heighten the cardiotoxic effects of cancer therapies on the risk of heart failure, myocardial infarction, and stroke, we wil use the Danish population registry, a rich source of detailed longitudinal data. Data on cardiovascular risk factors, therapies, and cardiac outcomes are all captured prospectively. Much of our understanding of cardiovascular risk among lymphoma survivors comes from randomized clinical trials, which typically include the healthiest cancer patients. It is imperativ to include patients with a full range of cardiovascular risk factors, which are found in our data. f hypertension, dyslipidemia, and diabetes contribute more than additively to cardiovascular damage in the presence of anthracyclines or radiation therapy, lymphoma survivors who had both pre-existing risk factors may require aggressive risk reduction strategies after treatment completion. Findings from this study will inform a future study to develop risk prediction models for myocardial infarction, stroke, and heart failure. Risk stratification of lymphoma survivors wil enable clinicians to identify high-risk survivors for more intensive cardiovascular preventive efforts.